Field of the Invention
Embodiments of the invention generally relate to compounds that are useful as selective ligands for the serotonin receptor 2B (5-HT2B). Some of the compounds are synthetic non-natural ligands which have a relatively strong interaction with 5-HT2B compared to naturally occurring compounds (some of which are identified for the first time herein as ligands for 5-HT2B). Because the compounds, both naturally occurring and synthetically produced, function as ligands for 5-HT2B they will have application in, for example, the treatment and/or prevention of nervous system disorders such as Alzheimer's disease.
Background of the Invention
Serotonin (or 5-hydroxytryptamine, 5-HT) is a well-known neurotransmitter of the peripheral and central nervous systems (PNS and CNS).[1, 2] 5-HT is often associated with mood disorders such as depression and schizophrenia; however the role of 5-HT extends beyond controlling mood. Specifically, 5-HT has been shown to be involved in controlling food intake, gastrointestinal function, cardiovascular function, cell development, drug seeking behavior, and pain.[2, 3] The numerous functions of 5-HT can be attributed to the diversity in its receptors. [4] Presently there are seven 5-HT receptor families (designated 5-HT1-7) with each having their own unique pharmacology. Thus, there is a need for small molecules to selectively target 5-HT receptor sub-types to treat a wide variety of conditions and/or diseases associated with 5-HT signaling.
The Serotonin receptor 2 (5-HT2) subfamily consists of three subtypes: 5-HT2A, 5-HT2B and 5-HT2C.[5] The 5-HT2B receptor was initially identified in isolated preparations of the rat fundus and was found to regulate contractions.[6] In humans, 5-HT2B can be found in both the peripheral and central nervous system.[5] The 5-HT2B receptor binds the neurotransmitter serotonin and mediates many of the central and peripheral physiologic functions of serotonin. 5-HT2B receptors regulate serotonin release via the serotonin transporter, and are important both to normal physiological regulation of serotonin levels in blood plasma, and with the abnormal acute serotonin release produced by drugs such as MDMA. Some effects of serotonin on the CNS include presynaptic inhibition, neuronal sensitization to tactile stimuli, mediation of some of the effects of hallucinogenic substituted amphetamines, and behavioral modifications.
Recently there has been a resurgence in developing selective antagonists for 5-HT2B for the treatment of irritable bowel syndrome, migraine, pulmonary hypertension, and drug abuse.[7] There is also evidence that antagonists of 5-HT2B may also be suitable neuroprotectants useful for treating neurodegenerative diseases.[8] Despite the potential use for 5-HT2B antagonists, much work still needs to be done. A notable challenge in developing ligands for 5-HT2B is that of selectivity.[9] 5-HT2B shares approximately 46-50% sequence identity with 5-HT2A/C and their homology within the transmembrane domain (which contains the 5-HT binding pocket) is higher than 70%.[5] Thus, the design of selective ligands targeting 5-HT2B over 5-HT2A/C is a challenge. Currently, there are a limited number of ligands selective for 5-HT2B Among the available ligands, some of the more commonly used structural scaffolds are: arylureas (1), arylpiperazines (2), indolonapthyridines (3), pyrimidines (4), and therahydro-β-carbolynes (5) (FIG. 1).[7]
The role of natural products in helping to understand the biochemical bases of human diseases is well established.[12] One class of natural products with a long history of having beneficial biological effects are chromones (6) (FIG. 2).[13] Chromones are heterocyclic compounds readily identified by their benzoannelated γ-pyrone core and have been isolated from both terrestrial and marine sources.[13] Compounds containing the chromone core have shown a broad range of activities, which include but are not limited to antioxidants[14], anti-inflammatory[15], antivirals[16], and neuroprotectants[17, 18]. Within the chromone superfamily smaller subfamilies exist and are identified most often by the position and nature of the substituent on the “A” ring. Examples of these subfamilies are flavones (7), isoflavones (8) and 2-(2-phenylethyl)chromones (9) (FIG. 2). Among these, the 2-(2-phenethyl)chromones (9) are the least understood.
Neurodegenerative diseases affecting the central nervous system (CNS) are widely spread among the population.[20] Consequently, tremendous research effort has been directed towards the development and application of small molecules to study the proteins involved in these CNS disorders.[21] Thus far, most of the research on the therapeutic value of chromones as related to CNS disorders has been correlated only to their antioxidant properties.[14] Until recently, little attention has been paid to the ability of chromones to serve as small molecule modulators of enzymes and receptors within the CNS.[23-25] Lately, 2-(2-phenylethyl)chromones (9), a relatively small and under-explored class of chromones have shown promise as potential tools to study CNS related disorders.[26] Unlike the flavonoids, these chromones possess a phenylethyl substituent at C2 and to date less than 100 congeners of 2-(2-phenylethyl)chromone have been isolated and characterized.[19] Yoon et. al. isolated 5-hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 10) from Imperata cylindrical and showed that this compound had neuroprotective activity against glutamate induced excitotoxicity in primary cultures of rat cortical cells.[17] The neurotoxic effects of glutamate have been shown to involve not only glutamate receptors but also non-glutamate receptors, ion channels, and transporters.[27,28] Thus, elucidation of the potential molecular target(s) of 5-HPEC would be necessary in order to further study the role of this type of compound in their CNS neuroprotection mechanism and to develop potential therapeutics.